Process for the preparation of 5-aryl-2,3-dihydro-2,2(or 3,3)dimethyl-5h-imidazo (2,1-a)isoindol-5-ols and 2(4,4(or 5,5)dimethyl-2-imidazolin-2-yl)benzophenone acid addition salts

ABSTRACT

NOVEL COMPOUNDS HAVE BEEN PREPARED WHICH HAVE USEFUL PHARMACOLOGICAL ACTIVITY AS WELL AS INTERMEDIATES FOR THEIR PRODUCTION. SOME OF THE PROCESSES HAVE UTILITY FOR THE PRODUCTION OF OTHER PHARMACOLOGICALLY ACTIVE COMPOUNDS THE ACTIVE COMPOUNDS OF THIS INVENTION ARE THOSE OF THE FOLLOWING FORMULAS:   2-(2-(R1-CO-),R2,R3-PHENYL),R4,R5-2-IMIDAZOLINE . HX AND   5-R1,R2,R3,R4,R5-2,3-DIHYDRO-5H-IMIDAZO(2,1-A)ISOINDOL-   5-OL   WHEREIN R1 IS SELECTED FROM THE GROUP CONSISTING OF PHENYL, MONOHALIPHENYL, DIHALOPHENYL, MONP(LOWER) ALKYLPHENYL, DI(LOWER)ALKYLPHENYL, TRIFLUOROPMETHYLPHENYL, MONO(LOWER)ALKOXYPHENYL, DI(LOWER)ALKOXYPHENYL, THIENYL, PYRIDYL, FURYL, AND TETRAHYDRO--2-NAPHTHYL, R2 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN HALOGEN, AMINO, (LOWERALKYLAMINO, (LOWER)ALKYL AND (LOWER)ALKOXY, R3 IS HYDROGEN WHEN R2 AND R3 ARE DISSIMILAR AND WHEN R2 AND R3 ARE THE SAME THEY ARE BOTH SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGEN, (LOWER)ALKYL AND (LOWER)ALKOXY; R4 AND R5 ARE LOWER ALKYL AND ATTACHED TO THE SAME CARBON ATOM; X IS THE ANION PORTION OF A PHARMACOLOGICALLY ACCEPTABLE ACID-ADDITION SALT.

United States Patent PROCESS FOR THE PREPARATION OF -ARYL-2,3-

DIHYDRO 2,2(0R 3,3)DIMETHYL-SE-I1VIIDAZO [2,1-a1ISOINDOL 5 OLS AND2(4,4(0R 5,5)DI- METHYL 2 I1VHDAZOLIN 2-YL)BENZOPHE- NONE ACID ADDITIONSALTS Theodore S. Sulkowski, Wayne, and Albert A. Mascitti, Norristown,Pa., assignors to American Home Products Corporation, New York, N.Y.

No Drawing. Original application Feb. 12, 1970, Ser. No. 10,984, nowabandoned. Divided and this application Jan. 26, 1972, Ser. No. 221,051

Int. Cl. C07d 49/34 US. Cl. 260-294.8 R 2 Claims ABSTRACT OF THEDISCLOSURE Novel compounds have been prepared which have usefulpharmacological activity as well as intermediates for their production.Some of the processes have utility for the production of otherpharmacologically active compounds. The active compounds of thisinvention are those of the following formulas:

wherein R is selected from the group consisting of phenyl,monohalophenyl, dihalophenyl, mono(lower) alkylphenyl,di(lower)alkylphenyl, trifiuoromethylphenyl, mono(lower)alkoxyphenyl,di(lower)alkoxyphenyl, thienyl, pyridyl, furyl, andtetrahydro-Z-naphthyl; R is selected from the group consisting ofhydrogen, halogen, amino, (lower)alkylamino, (lower)alkyl and (lower)alkoxy; R is hydrogen when R and R are dissimilar and when R and R arethe same they are both selected from the group consisting of hydrogen,halogen, (lower)alkyl and (lower)alkoxy; R and R are lower alkyl andattached to the same carbon atom; X is the anion portion of apharmacologically acceptable acid-addition salt.

This is a division of application Ser. No. 10,984 filed Feb. 12, 1970,now abandoned.

This application discloses processes which may be applicable in theproduction of compounds disclosed in the US. patent application, Ser.No. 757,792, filed Sept. 5, 1968, now US. Pat. 3,763,178. The novelcompounds of this invention exhibit antidepressant activity but, unlikethe compounds disclosed in Ser. No. 757,792, do not possess anorexiantactivities at therapeutic dosages.

This invention relates to pharmacologically active 5-aryl-2,3-dihydro-2,2 (or 3,3) dimethyl-SE-imidazo [2,1-a] isoindol-S-olsand 2(4,4(or 5,5)dimethyl-2-imidazolin-2- yl)benzophenone acid additionsalts and processes for their production. The intermediate compoundsproduced by the processes of the invention are also novel.

The new and novel compounds which are included 3,803,155 Patented Apr.9, 1974 within the scope of this invention are represented by thefollowing formulae:

N Rt N R4 i R5 R:

N N R i R I R: H H: OH

I II

0 O M R N I R2 and R N-CHr-CNHR RI R5 Re I N-R. OH

R1 v R:

III IV wherein R is selected from the group consisting of phenyl,monohalophenyl, dihalophenyl, mono(lower) alkylphenyl,di(lower)alkylphenyl, trifluoromethylphenyl, mono (lower)alkoxyphenyl,di(lower)alkoxyphenyl, thienyl, pyridyl, furyl andtetrahydro-Z-naphthyl; R is selected from the group consisting ofhydrogen, halogen, amino, lower alkylamino, lower alkyl and loweralkoxy; R is hydrogen, when R and R are dissimilar and when R and R arethe same they are both selected from the group consisting of hydrogen,halogen, lower alkyl and lower alkoxy; R and R are selected from thegroup consisting of hydrogen and lower alkyl with the provisos that inFormulae I, II and HI both R, and R are lower alkyl and in Formulae Iand II both R, and R are attached to the same carbon atom; R is selectedfrom the group consisting of hydrogen, lower alkylsulfonyl,phenylsulfonyl, monohalophenylsulfonyl, dihalophenylsulfonyl,mono(lower)alkylphenylsulfonyl, di (lower)alkylphenylsulfonyl and loweralkoxyphenylsulfonyl with the proviso that in Formula IV R, is otherthan hydrogen; and X is an anion portion of a pharmacologicallyacceptable acid-addition salt.

As employed herein the term (lower)alkyl is meant to include straightand branched chain hydrocarbon moieties of from 1 to about 4 carbonatoms such as methyl, ethyl, propyl, i-propyl and butyl. The term(lower)alkoxy is used to include hydrocarbonoxy groups which containfrom 1 to about 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxyand hexoxy. The term halogen and halo as used herein are meant toinclude bromine, fluorine, chlorine and iodine.

Those skilled in the art will appreciate that the compounds of FormulaeI and II are tautomers. It has been found that the base form (I) existsas the tricyclic imidazoisoindole form and the acid-addition salt (II)exists as the benzophenone form. The nature of the reaction by which thecompounds are prepared does not allow the position of the gem dialkylgroups to be fixed with certainty. When the compound exists as thebenzophenone type form, it is impossible to fix the position of the gemdialkyl groups because of the proton shift due to the -NH-C=N- group.Hence, the 2-(gem dialkyl-2- imidazolin-Z-yl)benzophenone acid-additionsalts are named as 4,4(5,5)dialkyl substituted compounds. This is inconformity with the nomenclature for imidazole type compounds set forthin Heterocyclic Compounds, R. C. Elderfield, editor, vol. 5, pp. 198,199 and 238, John Wiley and Sons, Inc., New York, 1957. When theimidazoisoindol-ol form of benzophenone tautomer is formed, thetautomerism of the HNC=N moiety does not permit any absolute predictionas to positioning of the gem dialkyl group in the imidazoisoindol-olform. When the'steric influence of the gem 'dialkyl group is considered, the probability is great that the product obtained is a2,2-dialkyl compound. Gas chromatographic studies indicate a singlecompound is isolated and not a mixture of the 2,2-dialkyl and3,3-dialkyl isomers. As the available evidence does not conclusivelyeliminate the possibility of the formation of the 3,3-dialkyl compound,the alternative nomenclature is employed herein, although it is believedthat the structure is in actuality a2,2-dialkyljg-imidazo[2,1-a1isoindol-5-ol.

The compounds of Formulae I and II may be prepared by contacting theappropriate phthalimidine with sulfuric acid and subsequently treatingthe product with base:

wherein R R R R R and R are the same as hereinabove defined. Inaddition, this method is operable for the production of compoundswherein R and R are hydrogen.

Concentrated sulfuric acid of about 80 to about 100% strength iscomployed in converting Compound V to Compound VI. Generally, nocriticality attaches to the use of a particular basic compound when thesulfate salt is treated to prepare the imidazoisoindol-ol base form. Forexample, sodium carbonate, sodium hydroxide, potassium hydroxide orsodium bicarbonate may be used. When the tautomeric acid-addition saltis prepared, the preferred method is to saturate a lower alkanolicsolution of the base form of the compound with hydrogen chloride gas.Suitable lower alkanols include methanol, ethanol and propanol.

The intermediate sulfonated phthalimidines may be prepared as follows:

wherein R R R R R and R are the same as hereinabove defined and X is ahalogen atom. In addition, R and R may be hydrogen when intermediates:are being prepared for making compounds wherein the imidazo moiety isunsubstituted. The sulfonation is usually conducted in pyridine althoughother suitable organic or aqueous solvents with a base such as sodiumcarbonate or triethylamine may be employed. The reactants are refluxedfor about 12 to 24 hours, then the solvent is evaporated and the residueis partitioned between water wherein R R R R R and R are the same ashereinabove defined.

The imidazoisoindolone compounds may be prepared by condensing al,l-dialkylethylenediamine 'with the appropriate 0- (substitutedcarbonyl)benzoic acid:

R1 wherein R R R R and R are the same as hereinabove defined.

The imidazoisoindolones may be prepared by refluxing the reactants in awater immiscible organic solvent such as toluene, benzene, xylene,chloroform, carbontetrachloride, pyridine, etc. The flask should beequipped with a water separator and the usual period of reflux is 12-24hours. The solution is then extracted with water and the organic layeris evaporated in vacuo to a solid residue. On recrystallization fromethanol, ethyl acetate, hexane-acetone, chloroform, etc. theimidazoisoindolone is obtained in good yield.

The compounds of Formulae I and orally to mammals.

The compounds have been orally administered to a group of six mice (3males and 3 females). One hour later the animals are challenged withreserpine, 2.5 mgJkg. administered intraperitoneally. The degree ofptosis for II are pharmacologically active as antidepressant agents whenadministered each eye was determined at one and two hours posttreatment. Prevention of reserpine ptosis is an indication ofantidepressant activity. See Rubin et al., J. Pharmacol. Exp. Therap.120, 125 (1957). Controls are simultaneously run with amphetamine andTofranil. The compounds of Formulae I and II were found to be active inmice at a dose of about 0.95 mg./kg. when administered orally.

The compounds have also been tested for anorexiant activity according tothe following procedure:

Male Charles River rats between 120 and 140 grams are trained to drinksweetened condensed milk from a graduated drinking tube. After a shortlearning period the animals are placed on a routine of water ad lib for24 hours, standard laboratory chow for 22 hours and sweetened condensedmilk for 2 hours. The volume of milk consumed is measured at 30 minutesas well as 2 hours. The animals are weighed every day. This schedule ismaintained 5 days a Week over a period of several months. Drug trialsare run on Thursdays and changes in milk consumed and 24 hour weightchanges are compared to the average of the two days before drugadministration. Animals are tested as groups of six and one group isgiven saline each week to serve as controls. Drugs are usuallyadministered intraperitoneally in saline or orally in water.

The compounds of the invention did not inhibit appetite when treated atdosage levels of up to mg./kg. of body weight, p.o.

The following examples have been added to illustrate but not to limitthe scope of the invention:

EXAMPLE I A solution of 50 g. of o-(p-chlorobenzoyl)benzoic acid, 100ml. of toluene and 40 ml. of 1,2-diamino-2-methylpropane is refluxed ina flask equipped with a water separator. After refluxing for seventeenhours, the solution is extracted with water and the organic portionevaporated in vacuo to a solid residue. On recrystallization fromethanol, there is obtained 9b-(p-chlorophenyl)-1,2,3,9b-tetrahydro-2,Z-dimethyl 5 E I imidazo[2,1-a]isoindol-S-one, M.P.1324 C.

Analysis.Calcd for c rr clmo (percent): C, 69.34; H, 5.17; N, 8.99; Cl,11.11. Found (percent): C, 69.21; H, 5.40; N, 8.65; C1, 11.30.

In a similar manner, reacting appropriate 1,1-dialkylethylene diaminewith o-benzoylbenzoic acids, there is obtained:

1 ,2,3 ,9b-tetrahydro-2,2-diethyl-9b-phenyl-5gimidazo[2,1-a]isoindol-S-one;

2,2-diethyl-9b-(3,4-diiodophenyl)1,2,3,9b-tetrahydro-Sg-imidazo[2,1-a]isoindol-5-one;

9b-( 3 ,4-diethoxyphenyl) 1 ,2,3 ,9b-tetrahydro-2,2-dimethyl-Sg-imidazofl,1-a]isoindol-5-one;

2-ethyl-9b- (4-hexylphenyl) -1,2,3 ,9b-tetrahydro-2 methyl-5 E -imidazo[2,1-a] isoindol-S-one;

7-amino-9b- (p-fluorophenyl)-1,2,3 ,9b-tetrahydro-2,2-dipropyl-SE-imidazo [2,1-a1isoindol-5-one; and

7-chloro-9b- (4-ethylphenyl)-1,2,3,9b-tetrahydro-2-methyl-Z-propyl-SE-imidazo [2, 1-a] isoindol-S-one.

EXAMPLE II A solution of 50 g. of o- (p-fluorobenzoyDbenzoic acid,

150 m1. of toluene and 75 ml. of 1,2-diamino-2-methyl- 6tetrahydro-2,2,7-trimethyl 9b phenyl-5-imidazo[2,la]isoindol-5-one; and1,2,3,9b tetrahydro-2,2-dimethyl-9b-phenyl-9-protpyl-SIT-imidazo[2,1-a]isoindol '5 one are prepared.

EXAMPLE HI A solution of 40 g. of o-benzoylbenzoic acid, 60 ml. ofl,2-diamino-Z-methylpropane, and 150 ml. of toluene i's refluxed in aflask equipped with a water separator. After refluxing eight hours thesolution is extracted with water and the toluene portion is evaporatedto dryness. The residue is recrystallized from ethanol to obtain1,2,3-9btetrahydro 9b phenyl-2,Z-dimethyl-Sg-imidazo[2,l-a]isoindol-S-one, M.P. 146-9 C.

Analysis.--Calcd for C H N O (percent): C, 77.67; H, 6.52; N, 10.07.Found (percent): C, 77.35; H, 6.88; N, 10.15.

Repeating the above procedure, the following compounds are prepared:

9b- (3 ,4-dichlorophenyl) -1,2,3 ,9b-tetrahydro-2,2-dimethyl- 5 I-in1idazo[2,1,-a]isoindol-5-one;

2,2-diethyl-9b- (p-fluorophenyl-1,2,3,9'b-tetrahydro-5gimidazo[2,1-a1isoindol-5-one; and

1,2,3,9b-tetrahydro-2,2-dimethyl-9b- (p-tolyl) -5 I1-imidazo[2,1-a]isoindol-5-one.

EXAMPLE IV A solution of 35 g. of o-(p-bromobenzoyl)benzoic acid, 125ml. of toluene, and 50 ml. of 1,2-diamino-2-methylpropane is refluxed ina flask equipped with a water separator. After refluxing six hours, thesolution is extracted with water. The toluene layer is evaporated todryness in vacuo. On recrystallization from dilute alcohol there isobtained 9b(p-bromophenyl)-1,2,3,9b-tetrahydro-2,2-dimethyl-SE-imidazo[2,1-a]is0indol-5-one,M.P. 133-5 C.

Analysis.-Calcd for C H N BrO (percent): C, 60.51; H, .480; N, 7.84.Found (percent): C, 60.80; H, 4.91; N, 7.91.

EXAMPLE V When the procedure of Examples I-IV is repeated to condense anappropriate 1,1-dialkylethylene diamine with a o-ketoacid, the following2,2-dialkyl-9b-aryl-1,2,3,9btetrahydro 5g imidazo[2,1-a]isoindol-5-onesare produced:

4 N s m 3 N-H wherein R R R R and R are as follows:

R; Ra Ra R4 R5 p-Iodppheuyl 7-bromo. Hydrogen MethyL. Methyl. 3,4-drmethylphenyl. B-methoxy do .do Ethyl. p-Methoxyphenyl 7-ch1or08-chloro do Methyl. Trifluoromethylpheuyl.,- 7-methyl- Hydrogern.Ethyl..- Ethyl.

amino. 2, 5-dlbrom0phenyl 7-methyl; 8-rnethyl.-- MethyL. Methyl. 3,4-dimethoxyphenyl 6-ethoxy Hydrogen do D0. 2-thien 7- methoxy S-methoxy-Butyl..- Butyl. p-Propoxyphen 9-1odo Hydrogen.- MethyL- Methyl. -pyr yl7-fluoro 8-fiuoro ...do Butyl. 2,5-d1p1'opoxyphenyl Hydrogern- Hydrogen.do Methyl 2-fur 7-ethyl dn jn D 3, 4-diethylphenyl B-propyld0 do Do.

ammo. Tetrahydro-Z-naphthyl--. 7-ethyl 9-ethyl PropyL- Ethylo-Chlorophenyl Hydrogen Hydrogen Methyl" Methyl Phenyl B-ethyl do do Do.2,5-dibutylphenyl Hydrogen do do Do. Phenyl ,dn dn Ethyl.-- DO.p-Chlorophenyl 7-ethoxy .do MethyL. Do. m-Ghlorophenyl Hydrogen do do.Do.

EXAMPLE VI A mixture of 30 g. of9b-(p-chlorophenyl)-1,2,3,9btetrahydro-2,2-dimethyl 5 E imidazo[2,l-a]isoindol-5- one. as prepared in Example I, and ml. of 50%hydrochloric acid is heated in a steam bath. Solution occurs on heatingfor ten minutes; then solid begins to precipitate immediately. Themixture is cooled, filtered and washed with acetone to obtain2-(2-amino-2-methylpropyl)-3-(p-chlorophenyl)-3-hydroxyphthalimidinehydrochloride, M.P. 230-2 C.

This hydrochloride salt is neutralized with sodium carbonate solution toobtain the corresponding phthalimidine base, M.P. 20810 C.,(recrystallized from ethanol).

Analysis.Calcd for C H N Clo' (percent): C, 65.35; H, 5.79; N, 8.47; Cl,10.72. Found (percent): C, 65.48; H, 5.75; N, 8.43; CI, 10.88.

Similarly, the following compounds are prepared from the other2,2-dialkyl-9b-aryl-l,2,3,9b-tetrahydro-5g-irnidaz[2,1-a]isoindol-5-onesof Example I:

2(2-amino -,2 ethylbutyl) 3 hydroxy-3-(3,4-diiodophenyl)phthalimidine;

2-(Z-amino-Z-methylpropyl) 3 (3,4-diethoxyphenyl)-3-hydroxyphthalimidine;

2-(2-amino-2-rnethyl'butyl) 3 '(4-hexylphenyl)-3-hydroxyphthalimidine;

6-amino-2-(2-amino 2 propylpentyl) 3(p-fluorophenyl)-3-hydroxyphthalimidine; and

2-(2-amino 2 methylpentyl)-6-chloro 3(p-ethylphenyl)-3-hydroxyphthalimidine.

EXAMPLE VII A mixture of 45 g. of9b-(pfluorophenyl)-1,2,3,9btetrahydro-2,2-dimethyl gimidazol[2,1-a]isoindol- 5-one, as prepared in Example II, and 150 ml.of 50% hydrochloric acid is heated in a steam bath. After ten minutes aclear solution forms; then solid begins to precipitate. The mixture isheated for an additional ten minutes, then cooled, filtered and washedwith acetone. The solid obtained is2-(2-amino-2-methylpropyl)-3-(pfluorophenyl)-3-hydroxyphtha1imidinehydrochloride, hydrate M.P. 177180 C. dec.

The hydrochloride salt is neutralized with sodium carbonate solution toobtain the phthalirnidine base, M.P. 19'69 C. p

Amzlysis.--Calcd for C H N FO (percent): C, 68.78; H, 6.09; N, 8.91.Found (percent): C, 68.83; H, 6.18; N, 8.99. I

Similarly, 2-(Z-amino-Z-methylpropyl)-3-(3-bromo-ptolyl)-3-hydroxyphthalimidine;2-(2-amino-2-rnethylpropyl)-3-hydroxy-6-methyl-3-phenylphthalimidine;and 2.- (Z-amino-Z-methylpropyl) 3hydroxy-3-phenyl-4-propylphthalimidine.

EXAMPLE VIII A mixture of 47 g. of 1,2,3,9b-tetrahydro-9b-phenyl-2,2-dimethyl-5g-imidazo[2,1-a]isoindol 5 one, as prepared'in ExampleIIL'and 150 ml. of 50% hydrochloric acid is heated on a-steam bath.Clear solution forms within fifteen minutes then reprecipitation occurs.After heating an additional five minutes, the mixture is cooled andfiltered to obtain2-(Z-amino-Z-methylpropyl)-3-hydroxy-3-phenylphthalimidinehydrochloride, M.P. 2525 C. (dec.).

The above-prepared hydrochloride salt is neutralized with sodiumcarbonate solution to obtain the phthalimidine base, M.P. l72-3 C.

Analysis.-Calcd for C T-1 N 0 (percent): C, 72.94; H, 6.80; N, 9.45.Found (percent): C, 72.80; H, 6.93; N, 9.32.

Repeating the above procedure, the following compounds are prepared:

2-'-(2-amino 2- methylpropyl)-3-(3,4-dichlorophenyl)-S-hydroxyphthalimidine;

2-(2-amino-2-ethylbutyl) 3 (p-fluorophenyl)-3-hydroxyphthalimidine; and

2-(2-amino-2-methylpropyl) 3 hydroxy-B-(p-tolyl) phthalimidine.

8 EXAMPLE 1x When the procedure of Examples VI-IX is repeated tohydrolize an appropriate2,2-dialkyl-9b-aryl-1,2,3,9'btetrahydro-SE-imidazofl,1-a]isoindol-5-one,as described in Example V, the corresponding2-(2-amino-2,2-dialkylethyl)-3-aryl-3-hydroxyphthalimidine hydrohalideis afforded which is then neutralized to produce the bases thereofhaving the formula:

wherein R R R R and R are as follows:

R; R2 Ra R4 R -Iodophenyl 7-bromo Hydrogem. MethyL. Methyl.

BA-dimethylphenyh. B-methoxy- .do d0 Eth p-Mcthoxyphenyl 7 -cl1l0ro8-chloro do Methyl.

Trifluoromcthylphenyl 7-1nethy1- Hydrogen Ethyl-.. Ethyl.

amino.

2,5-dibromophenyl- 7-methyl... Sanethyl.-. Methyl" Methyl.3,4-dimethoxyphenyl...-- 6-ethoxy Hydrogennlndonu. Do. 2-thieny17-methoxy 8-methoxy Butyl..- Butyl. p-Propoxyphenyl. .9-i0do HydrogenMethyL- Methyl. 2-pyrid 7fluoro 8-fiuoro .110"--. Butyl.2,5-dipropoxyphenyl Hydrogen Hydrogen. do Methyl 2-furyl 7-ethyl dn doDo. 3,4-diethy1phenyl S-propyl- -do do Do.

ammo.

Tetrahydr0-2-naphthyl... 7-ethyl.. 9-ethyl. PropyL- Ethyl.

o-Ghlorophenyl Hydrogen Hydrogern. MeithyL. Methyl.

S-ethyl d D Do. en n in Ethyl. D0. p-Ghlorophenyl 7-ethoxy do MethyL-Do. m-Chlorophcnyl Hydrogen do do Do.

EXAMPLE XI The acid chloride prepared from 26 g. ofo-(p-chlorobenzoyl)benzoic acid is dissolved in 40 ml. of acetone and isadded dropwise with stirring to 35 ml. of 1,2-diamino-Z-methylpropaneand ml. of pyridine. The mixture is stirred and refluxed for one hourthen evaporated to dryness in vacuo. The residue is slurried with waterand separated by filtration. On recrystallization from ethanol there isobtained 2-(2-amino-2-methylpropyl) 3(-p-chlorophenyl)-3-hydroxyphthalimidine, M.P. 208-210 C.

In a similar manner, the acid halide of appropriate o-benzoylbenzoicacids are acylated to afford the following compounds:

2-(2-amino-2-methy1propyD-3-(p-fluorophenyl)-3-hydroxyphthalimidine,M.P. 177-180 C.;

2- (2-amino-2-methylpropyl -3-hydroxy-3 -phenylphthalimidine, M.P. 1723C.; and

2-(2-amino-2-rnethylpropyl)-3-(p-bromophenyl)-3-hydroxyphthalirnidine,M.P. 194-6 C.

9 EXAMPLE XII A mixture of 30 g. of 2-(2-amino-2-methylpropyl)-3-(p-chlorophenyl)3-hydroxyphthalimidine hydrochloride, as prepared inExample VI, 30 g. of p-toluenesulfonyl chloride and 500 ml. of anhydrouspyridine is refluxed eighteen hours. The mixture is evaporated todryness. The residue is partitioned between ethyl acetate and Water. Theethyl acetate portion is dried over magnesium sulfate then evaporated todryness to a solid residue. On recrystallization from ethanol, there isobtained 9b-(-pchlorophenyl) l,2,3;9b-tetrahydro 2,2dimethyl-l-(ptolylsulfonyD-SE-imidazo[2,l-a1isoindol one, M.P. 184-6" C.

Analysis.Calcd for C H C1N O S (percent): C, 64.24; H, 4.97; N, 6.00;CI, 7.60; S, 6.87. Found (percent): C, 63.99; H, 4.83; N, 6.07; Cl,7.60; S, 6.80.

A solution of g. of the above-prepared 9b-(p-chlorophenyl) 1,2,3,9btetrahydro-2,2-dimethyl-1-(p-tolylsulfonyl)-5g-imidazo[2,1-a]isoindol-5-oneand 25 ml. of 85% sulfuric acid is allowed to stand at room temperaturefor two hours. The reaction mixture which contains the sulfate salt of4'-chloro-2-(4,4(5,5)-dimethyl-2-imidazolin-2-yl)benzophenone isquenched with several volumes of ice water and made basic withconcentrated sodium hydroxide solution. The precipitated solid isseparated and washed with water. On recrystallization from ethanol thereis obtained 5-(p-chlorophenyl)-2,3-dihydro- 2,2(or 3,3)dimethyl-SH-imidazo[2,1-a]isoindol 5-01, M.P. 3 C.

Analysis.-Calcd for C H N OCl (percent): C, 69.12. 'H, 5.49; N, 8.96;CI, 11.34. Found (percent): C, 68.98; H, 5.41; N, 9.05; C1, 11.49.

IR (KBr) l637cm.- 2222-2739 cm. U.V. (95% EtOH):

max. 222 mu (e=22,200)

max. 263 m (-e=6,000)

max. 272 m, (5:5,700)

(pH 1) max. 263 mp. (e=12,960)

The compound of Example XII possesses in addition to its antidepressantactivity the property of markedly redncing sleep at dosage levels whichproduce no signs of agitation or stimulation.

EXAMPLE XIII A mixture of 35 g. of 2-(2-amino-2-methylpropyl)-3-(p-chlorophenyl)-3-hydroxyphthalimidine hydrochloride, as prepared inExample VI, g. of p-toluenesulfonyl chloride and 125 ml. of anhydrouspyridine is refluxed for three hours. The solution is evaporated todryness and the residue partitioned between ethyl acetate and water. Theethylacetate portion is evaporated to a solid residue. Onrecrystallization from ethanol there is obtained N-(Z- [3(p-chlorophenyl)-3hydroxy-Z-phthalimidinyl]-l,1-dimethylethyl)-p-toluenesulfonamide, M.P.225-7 C.

Analysis.Calcd for C H ClN O S (percent): C, 61.91; H, 5.20; N, 5.78;Cl, 7.31; S, 6.61. Found (percent): C, 61.83; H, 5.00; N, 5.63; CI,7.43; S, 6.82.

A solution of 15 g. of the above-preparedN-(2-[3-(pchlorophenyl)-3-hydroxy-2-phthalimidinyl]-l,l-dimethyl-'ethyl)-p-toluenesulfonamide and 40 ml. of 90% sulfuric acid is allowedto stand at room temperature for fortyfive minutes. The reaction mixturewhich contains the.

sulfate salt of 4'chloro-2-(4,4(5,5)-dimethyl-2-imidazolin-2-yl)benzophenone is quenchedwith several volumes of ice water and neutralized with concentratedsodium hydroxide solution. The solid is separated and washed with water.On recrystallization there is obtained 5-(p-chlorophenyl)2,3-di=hydro-2,2(or 3,3)-dimethyl-5 H-imidazo[2,

to dryness in vacuo. The residue is triturated with ethyl acetate andseparated by filtration. On recrystallization from ethanol-ethyl acetatemixture, there is obtained 4'- chloro2-(4,4(5,5)-dimethyl-2-imidazolin-2-yl)benzophenone hydrochloride, M.P.235-8 C. dec.

Analysis.-Calcd for C H N OCl-HCl (percent): C, 61.90; H, 5.19; N, 8.20;Cl, 20.30. Found (percent): C, 61.59; H, 5.29; N, 8.20; Cl, 20.53.

IR (KBr) 1670 cmr- 2558-2941 cm.- U.V. (isopropanol) max. 263 m(e=12,460)

EXAMPLE XIV A mixture of 32 g. of 2-(2-amino-2-methylpropyl)-3-(p-fluorophenyl)-3-hydroxyphthalimidine, 22 g. of p-toluenesulfonylchloride and 200 ml. of pyridine is refluxed for eight hours. Thesolution is evaporated to dryness in vacuo and the residue ispartitioned between ethyl acetate and water. The ethyl acetate portionis evaporated to dryness. The residue is recrystallized from ethanol toobtain N (2-[3-(p-fluorophenyD-3-hydroxy-2-phthalimidinyl] -1,1dimethylethyl)-p-toluenesulfonamide, M.P. 206-9 C.

Analysis.Calcd for C H N FSO (percent): C, 64.09; H, 5.37; N, 6.30.Found (percent): C, 64.25; H, 5.39; N, 6.30.

A solution of 22 g. of N-(Z-[3-(p-fiuorophenyl)3-hydroxy-2-phthalimidinyl] l, l-dimethyl ethyl) -p-toluenesulfonamide,and 50 ml. of sulfuric acid is allowed to stand at room temperature forforty-five minutes. The mixture which contains the sulfate salt of4'-fluoro-2-(4,4(5, 5 )-dimethyl-2-imidazolin-2-yl)benzophenone isquenched with several volumes of ice water and neutralized withconcentrated sodium hydroxide solution. The solid is separated andwashed with water. On recrystallization from ethylacetate there isobtained 5-(p-fluorophenyl)-2,3dihydro-2,2(or 3,3)dimethy1-5E-imidazo[2, 1-a]isoindol-5- o1, M.P. 194-6 C.

Analysis.Calcd for C H N FO (percent): C, 72.96; H, 5.78; N, 9.45. Found(percent): C, 72.88 H, 5.91; N, 9.45.

IR (KBr) 1658 cur- 2273-2278 cm.- U.V. EtOH):

max. 260 m (-e=5,760)

max. 272 my. (5:5,000)

(pH 1) max. 252 m (e=13,000)

On treating 5-(p-fluorophenyl)-2,3-dihydro-2,2-dimethyl-5 H-imidazo[2,1-a]isoindol-5-ol with hydrogen chloride, there is obtained4'-fiuoro-2-(4,4(5,5)-dimethyl-2-imidazolin-2-yl)benzophenonehydrochloride. M.P. 203-5 C.

Analysis.-Calcd for C18H17N2FO'HCl (percent): C, 64.96; H, 5.45; N,8.42. Found (percent): C, 64.79; H, 5.47; N, 8.39.

IR (KBr) 1658 cm.- 2600-2941 cm.- U.V. (isopropanol) max. 250 m(e=12,100)

EXAMPLE XV A mixture of 27.5 g. of 2-(Z-amino-Z-rnethylpropyD-3-hydroxy-3-phenyl phthalimidine, 20 g. of p-toluenesulfonylchloridevand 200 ml. of pyridine is refluxed for eight hours. Thesolution is evaporated to dryness. The residue is triturated with waterand separated by filtration. On recrystallization from 95% ethanol thereis obtained N- .(2 [3phenyl-3-hydroxy-2-phthalimidinyl]1,1-dimethfiethyl)-p-tolueue-sulfonamide,M.P. 197-200 C.

Analysis.-Calcd for C H N SO (percent): C, 66.64; H, 5.81; N, 6.22.Found (percent): C, 66.30; H, 5.70; N, 6.13.

A solution of 17 g. of Ill-(2-[3-phenyl-3-hydroxy-2-phthalimidinyl]-1,l-dimethylethyl)-p-toluenesulfonamide and 50 ml. of90% sulfuric acid is allowed to stand at room temperature for forty-fiveminutes. The solution which contains the sulfate salt 2(4,4(5,5)dirnethyl-Z- imidazolin-Z-yl)benzophenone is quenched with severalvolumes of ice water and neutralized with concentrated sodium hydroxidesolution. The solid is separated and washed with water. Onrecrystallization from ethanol there is obtained5-phenyl-2,3-dihydro-2,2-dihydro-2,2(or

, 12 On treating 5- (p-bromophenyl)-2,3-dihydro-2,2-dimethyl-SIi-imidazo [.2,l-a]isoindol-5-ol withhydrogen chloride there is obtained 4'-bromo-2-(4,4( 5,5-dimethyl-2-imidaz olin-2-yl)benzophenone, hydrochloride. M.P. 222-5" C.Analysis.Calcd for c,,H,,BrN -Hc1 (percent): C,

3,3)-dimethyl 5 H-imidazo[2,1-a]isoindol-5-ol, M.P. 211- 5 212 C. 54.91;H, 4.61; N, 7.12. Found (percent): C, 55.09; H,

Analysis.Calcd for C H N O (percent): C, 77.67; 4.67; N, 6.75. H, 6.52;N, 10. F t 6.64; N 07 (Perm) C 77 44 H IR (KBr) 1661 cm. ,2500-2941 m.

10 U.V. (isopropanol) max. 267 m (c=14,500) IR (KBr) 1645 emf, 2273-2790cm.- U.V. (95% EtOI-I): EXAMPLE XVII max. 260 m (:4,900) When theprocedure of Examples XIII-XVI is repeated max. 260 m (e=4,900) to reactappropriate 2-(2-amino-2-alkylalkyl-3-aryl-3-hy- (pH '1) max. 250 my.(e=13,480) 15 droxyphthalimidine hydrohalide with aryl or alkyl sulfonylOn treating 5-phenyl-2,3-dihydro-2,2(or 3,3)-dimethylhahdes there IS dthe follow1ng -([3-ary l-3- SH-imidazo[2,l-a1isoindol-5-ol with hydrogenchloride, hYdYOXY-l-phthalflmdmfll-11-E11a1kY1a1k?1)sqlfonamldes ail-ereis obtained 244,4(5,5) dimethyl z imidazolin 2 y1) (I) which are thencontacted with sulfuric acid to aiford benzophenone, hydrochloride, M.P.174-6 C. appropriate sulfate salts of 4,4(5,5)-dialkyl-2-imidazolin-Analysis' calc,d for cmHmNzoHcl (percent), C, Z-yI-phenyl aroylCompounds II which are neutralized to 68.68; H, 6.08; N, 8.90. Found(percent): C, 63.36; H, afford appropriate 2,2(or3,3)-d1alky-5-aryl-2,3-d1hydr0- 07; N, 3 g7Sg-imidazoiZ,l-a]isoindol-5-ols (IH) which may be acid- 1 ified e.g.hydrochloric acid, to afford the corresponding $6 1645 f: 21 E 9404,4(5,5)-dialkyl-2-imidazolin-2-yl phenyl aroyl compound (lsopropano) (E25 acid-addition salts (IV) e.g. hydrochloride, which Com- EXAMPLE XVIpounds I, II, III and IV are depicted by the following A mixture of 16.8g. of 2-(2-amino-2-methylpropyl)-3- formulae:

(p-bromophenyl)-3-hydroxyphthalimidine, 10 g. of p-tolu- 0 enesnlfonylchloride and 100 ml. of pyridine is refluxed for eight hours. Thesolution is evaporated to dryness and I the residue is partioned betweenethyl acetate and water. R2 EFNHSOtRY The ethyl acetate portion isevaporated to a solid residue. Ra R 011 recrystallization from ethanolthere is obtained -(2- s [3 (pbromophenyl)-3-hydrOXy-Z-phthalimidinyl]-1,1- 1dimethylethyl)-p-toluenesulfonamide, M.P. 2347 C.

Arzalysis.-Calcd for C H N BrSO (percent): C,

56.71; H, 4.76; N, 5.30. Found (percent): C, 56.91; H, N R 4.65; N,5.45. i

A solution of 11 g. of E-(Z-B-(p-hromophenyl)-3-hy- 40 A 5 droxy 2phthalimidinyl]-1,l-dimethylethyl)-p-t0luene- R sulfonarnide and 50 ml.of 90% sulfuric acid is allowed C: H I to stand at room temperature forforty-five minutes. The -1/2H2SO solution which contains the sulfatesalt of 4'-brorno-(4,4 (3:0 (5,5) dimethyl 2 imidazolin 2yl)benzophenone is R1 quenched with several volumes of ice water andneutraln ized with concentrated sodium hydroxide solution. The solid isseparated and washed with water. Onrecrystallizal tion from ethylacetate, there is obtained S-(p-bromophenyl) 2,3 dihydro-2,2(or3,3)-dimethyl-5g-imidazo' N N [2,1-a]isoindol-5-ol, M.P. 1924* c. in. R.

Analysis.-Calcd for C H N BrO (percent): C, I s l Rs 60.51; H, 4.79; N,7.85. Found (percent): C, 60.51; H, N N 4.82; N, 7.82. I 7 R I R R IR(KBr) 1639 cmr 2273-2778 cmr a UN. (95% EtOH): t 1

max. 224- m (e=24,400)

max. 263 my. (e=6,780) (III) max. 275 m (e=6,400)

(ph 1) 'max. 267 mu (e=13,640) wherein R R R R R -and R are definedbelow:

I I l R1 R2 R3 R4 R5 R1 p-Iodophenyl 7-hromoQ. Methyl.. Methyl Ethyl.3,4-dimethylphenyl B-methoxy d do" Eth Phenyl. p-Methoxyphenyl..7-eh1oro .do. Methyl... p-Chlorophenyl. Trifinoromethylphenyl.7-methylamino. Hydrogen" Ethyl... Ethyl Phenyl. 2,5-dibromophenyl7-methyl 8-methy1 MethyL"- Methyl p-bromophenyl. 3,4-dimethoxyphenyl .d0do 4ethylphenyl. 2-thien l 13111391"--. 131113 1"... 3.4-dimethylphenyl.p-PropoxyphenyL- MethyL.-- Methylun Phenyl. 2-pyridyl 7-fluorn rln B2,5-dichlorophenyl. 2,5-dipropoxyphenyl Hydrogen Hydrogem. hyl Pentyl.

-i l 7-ethyldo 3,4-dibromophenyl. 3,4-diethylphenyl... 8-propylamino dodo do p-Iodophenyl. Tetrahydro-Z-naphthyl 7-ethy1 Q-ethyl Propyl. Ethy1.p-Methoxyphenyl. o-ChlorophenyL-.. Hydrogen Hydrogen... Methyl Methy1plodophenyl. Pheny 8-ethyl "do ..d0 -.do 3,4difiuorophenyl.2,5-dibutylphenyL. Hydr p-Ethoxyphenyl. Pheny do do Ethyl .4103,4diethy1phenyl. p-Chlorophenyl 7-eth0xy -.do Methyl "dop-Fluorophenyl.

m-Ch1orophenyl Hydrogen do ..do .do p-Ethoxyphenyl.

EXAMPLE XVIII A solution of 21.5 g. of2-(2-aminoethyl)-3-(p-chlorophenyl) 3 hydroxyphthalimidine, 13.3 g. of ptoluenesulfonyl chloride and150 ml. of pyridine is allowed to stand at room temperature for eighteenhours. The mixture is quenched with water and extracted with ethylacetate. The ethyl acetate portion is evaporated to dryness and theresidue crystallizes on standing for three days. On recrystallizationfrom aqueous ethanol there is obtained 1E(2-{3-(p-chlorophenyl)-3-hydroxy-l-phthalimidinyl]ethyl)-p-toluenesulfonamide, M.P. 133-6 C.

Analysis.Calcd for C H N O SCl (percent): C, 60.32; H, 4.84; N, 6.12;Cl, 7.74. Found (percent): C, 60.54; H, 4.50; N, 6.08; Cl, 7.56.

A solution of 18 g. of N-(Z-[3-(p-chlorophenyl)-3-hydroxy 2phthalimidinyl]ethyl)-p-toluenesulfonamide and 50 ml. of 90% sulfuricacid is allowed to stand at room temperature for forty-five minutes. Thesolution containing the sulfate salt of 4'-chloro-2-(2-imidazolin-2-yl)*benzophenone is quenched with several volumes of ice water andneutralized with concentrated sodium hydroxide solution. The solid isseparated and washed with Water. On recrystallization fromdimethylacetamide there is obtained 5(p-chlorophenyl)-2,3-dihydro-5g-imidazo- [2,l-alisoindol-5-0l, M.P.208210 C. (dec.).

Analysis.-Calcd for C H N OCI (percent): C, 67.49; H, 4.60; N, 9.84; Cl,12.45. Found (percent): C, 67.18; H, 4.32; N, 9.68; Cl, 12.70.

IR (KBr) 1645 cm.- 23803000 cm.- U.V. (95% EtOH):

max. 223 m (e -19,000)

infl. 242.5 m (e=8,300)

max. 268.5 m (e=4,400)

max. 272 m (e=4,400)

(pH 1) max. 251 mu (e=11,000)

max. 264 m (e=l0,800)

EXAMPLE XIX When the procedure of Example XXII is repeated to react2-(2-aminoethyl)-3-aryl-3-hydroxyphthalimidine -or hydrohalides withappropriate aryl or alkyl sulfonyl halides, there is aliorded N (2[3-aryl-3-hydroxy-2- phthalimidinyl]alkyl)sulfonamides which arecontacted with sulfuric acid to afford sulfate salts of Z-imidazolin-2-yl-phenyl aroyl compounds which are neutralized to yield the following5-aryl-2,3-dihydro-5g-imidazo[2,1-a] isoindol-S-ols which are acidifiede.g. hydrochloric acid to produce their corresponding hereinafter listed2- imidazolin-2-yl phenyl aroyl compound acid-addition salts e.g.hydrochlorides.

2-imidazolin-2-yl phenyl aroyl rsorndo -5-0Ls compound hydrochlorides2-(2-imidazolin-2-yl) -3,4-

diiodobenzophenonehydrochloride.

yl)benzophenone hydrochloride.

2-(2-imidazolin-2-yl)-4-methylbenzophenone hydrochloride.

4 hexyl-2-(2-imidazolin-Z yl) benzophenone hydrochloride.

2,(2-imidazolin-2-yl) phenyl-2- thienyl ketone hydrochloride.

TABLE Continued 2-inridazolln-2-yl phenyl oroyl compound hydrochloridesglihlydro-frH-imidazo[2,1-a1isoindol- 7,8 dichloro-2,3-dihydro-5-phenyl-5H-irnidazo[2,1-a]isoindol-5cl.

2,3-dihydro-7,8-dimethoxy-S- phimyl-sH-inrrdazo[2,1-a]isoindol-2-(2-irnidazolin-2-yl)-4mcthylbenzophenone hydrochloride.2-(2-imidazolin-2-yl)-6-propylbenzophenone hydrochloride.4-bromo-2(2-imidazolin-Z-yl)- benzophenone hydrochloride.3,4-dichloro-2-(2-imidazolin-2yD- benzophenone hydrochloride.

4-fluoro-2-(2-imidazolin-2-yl)- benzophenone hydrochloride.

3-bromo-2-(2-imidazolin-2-yl)-4- methylbenzophenone hydrochloride.

5-brorn0-2-(2-imldazolin-2-yl) -4'- methylbenzophenone hydrochloride.

4,4 ,5-tribromo-2-(2-imidazolin-2- yl)berrzophenone hydrochloride.

2-(2-irnidazolin-2-yl)-2,4'-

dimethoxybenzophenone hydrochloride. 2,4-dibromo-2-(2-imidazolin-2-yl)benzophenone hydrochloride. 2-(2-imidazolin-2-yl)phenyl-(5,6,7,8-tetrahydro-2-naphthyl)- ketone hydrochloride.4-triflouromethyl-2-(2-imidazolin- Zfi-gbbenzophenone hydrochlor ride.Furyl-2-(2-imidazolr'n-2-yl)phenyl ketone hydrochloride.3-amino-4-chloro-2-(2-imidazolin- 2-yl)benzophenone dihydrochloride.5-chloro-2-(2-imidazolin-2-yD- benzophenone hydrochloride.2-(2-imidazolirr-2-yl)-4-methylbenzophenone hydrochloride.5-ethylamirro-2-(2-irnidazolirr-2- y l)benzophenone dihydrochloride.4,5-dichloro-2-(2-imldaz0lir1-2-yl)- benzophenone hydrochloride.2-(2-irnidazolin-2-yl)-4,5-dimethoxybenzophenone hydrochloride.

2-(2-irnidazolin-2-yl)-3-iodobenzophenone hydrochloride.4-anryl'2-(2-irnidazolin-2-yl)berrzophenone hydrochloride.2-(2-irnidazolin-2-yl)-5-propylbenzophenone hydrochloride.4-butoxy-2-(2-imidazo1in-2yl)- benzophenone hydrochloride. 2-(2-imidazolin-2 yl) -3 ,4-

dimethylbenzophenone hydrobenzophenone hydrochloride.

EXAMPLE XX A solution of 10 g. of 2-(2-aminoethyl)-3-hydroxy-3- EXAMPLEXXI A solution of 7 g. of N-(2-[3 phenyl-3-hydroxy-2- phthalimidinyl]ethyl)-p-toluenesulfonamide and 20 ml. of sulfuric acid is allowed tostand at room temperature for 30 minutes. The solution is quenched withice water and extracted with ethyl acetate. The aqueous portion isneutralized with concentrated sodium hydroxide solution. The solid isseparated and washed with water. On recrystallization from dimethylacetamide there is obtained5-phenyl-2,3-dihydro-5g-imidazo[2,1-]isoindol-5-ol, M.P. 207-210 C(dec.).

15 Analysis.-Calcd for C H N O (percent): C, 76.77; H, 5.63; N, 11.20.Found (percent): C, 76.63; H, 5.66; N,'11.00.

I IR (KBr) 1645 cm." 2300-3000 cmr U.V. (95 EtOI-I):

inf. 225 mp (e=l4,900) max. 268 mu (e=4,200) (pH 1 max. 250 m (e=l3,500)

On treating S-phenyl -2,3-dihydro-5g-imidazo[2,l-a]- isoindol-S-ol withhydrogen chloride, there is obtained 2- (2 imidazolin-Z-yl)benzophenonehydrochloride, M.P; 195-7 C. (dec.).

Analysis.Calcd for C H N O-HCI (percent): C, 67.03; H, 5.27; N, 9.77;CI, 12.36. Found (percent): C, 66.88; H, 5.33; N, 9.83; Cl, 12.50.

IR (KBr) 1650 cm.'- 2400-3200 cm. U.V. (95% EtOH) max. 250 m (e=12,800)

What is claimed is: 1. A process for the preparation of a compoundhaving the formula:

N- R I R.

N R I! I R! OH wherein R is selected from the group consisting ofphenyl, monohalophenyl, dihalophenyl, mono(lower)alkylphenyl,d1(lower)alkylphenyl, trifluoromethylphenyl, mono (lower) alkoxyphenyl,di(lower)alkoxyphenyl, thienyl, pyridyl, furyl andtetrahydro-Z-naphthyl; R is selected from the group consisting ofhydrogen, halogen, amino, lower alkylamino, lower alkyl and loweralkoxy; R is by drogen, when R and R are dissimilar and when R and R arethe same they are both selected from the group consisting of hydrogen,halogen, lower alkyl and lower alkoxy; R, and R are selected from thegroup consisting of hydrogen and lower alkyl which comprises treating acompound of the formula:

NCH:[NHRa -011 1 wherein R R R R and R are the same as defined above andR is selected from the group consisting of lower alkylsulfonyl,phenylsulfonyl, monohalophenylsulfonyl, dihalophenylsulfonyl,mono(lower)alkylphenylsulfonyl, di(lower)alkylphenylsulfonyl and loweralkoxy phenylsulfonyl with from about 80 to about 100 percent sulfuricacid to form a sulfate of the formula:

wherein R R R R and R are as above defined and then contacting saidsulfate with a base.

2. A process for the preparation of a compound having the formula: I

wherein R R R R and R are the same as defined above and R is selectedfrom the group consisting of lower alkylsulfonyl, phenylsulfonyl,monohalophenylsulfonyl, dihalophenylsulfonyl,mono(lower)alkylphenylsulfonyl, di(lower)alkylphenylsulfonyl and loweralkoxyphenylsulfonyl with from about '80 to about percent sulfuric acid.

References Cited Derwent Farmdoc Complete Specification Book No. 796,34, 397-34, 428, pages 743-761 (issued Nov. 12, 1968, received PatentOflice Scientific library Dec. 13, 1968), London, Derwent Publications.1 Sulkowski et al.; J. Org. Chem. vol. 32, pages 2180-4 (1967).

NATALIE "rnonsor, Primary Examiner US. Cl. X.R.

260--294.8 B, 294.8 C, 295 K, 295 T, 296 R, 296 T, 309.6, 309.7, 325,332.2 R, 346.2 R, 347.3, 517; 424Z63, 273

UNITED sTATEs PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,803,155 Dated April 9, 1974 lnventofls) Theodore S Sulko It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Change Column 9, line 29, Change "2o-3c." to --2o1-3c.--

Column 12, lines 50-59 complete the upper portion of the left handformula to read L (continued) J UNITED STATES PATENT OFFICE 6CERTIFICATE OF CORRECTION a 2 Pltent 3 .B03rl55 Dated a ti 1 2 1274Inventor) Theodore S Sulkowski, and Albert Mascitti It is certified'that error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 15, change the last formula to read N 4 1 ,A 5: R5 '5 2 i" Column16, change the right side of the last formula to-read 4 "'CH f-NHR 5Signed and sealed this 29th day of October 1974.

(SEAL) Attest:

C. MARSHALL DANN Commissioner of Patents McCOY M. GIBSON JR. AttestingOfficer

